Clinical Practice Guidelines and Recommendations by World Association of Perinatal Medicine and Perinatal Medicine Foundation: Reporting Suspected Findings from Fetal Central Nervous System Examination

Keywords

Guidelines, anomaly scan, fetal central nervous system, fetal anomalies, ultrasound

Introduction

Fetal central nervous system (CNS) abnormalities are relatively common.[1] Although some patients are at high risk for fetal CNS abnormalities, either because of a family history or due to exposure to teratogens such as congenital infections[2], the vast majority of fetal CNS abnormalities occur in patients without any fetal or familial/maternal risk factors for these anomalies. Therefore, the evaluation of the fetal CNS during the routine mid-trimester US scan, traditionally performed between 20 to 24 weeks of gestation, plays a central role in the prenatal diagnosis of these abnormalities, representing the gold standard for their detection.[1] However, the evaluation of fetal anatomy in the first trimester of pregnancy, including CNS, has drastically evolved in the past decade. This is the reason why the evaluation of the fetal head and spine have been recommended between 11 + 0 to 14 + 0 weeks’ gestation by the guidelines of the World Association of Perinatal Medicine (WAPM) recently published.[3] Furthermore, certain CNS anomalies can develop or being recognized only later on during the third trimester or even after delivery. Consequently, in cases where a third trimester scan is performed for any indication, some assessment of the fetal CNS is warranted.

Whenever possible, when a suspected congenital anomaly is detected, patients should be referred to specialized centers for expert evaluation (referral scan) and a definitive diagnosis.[4] This evaluation includes a detailed examination of the CNS commonly referred to as “fetal neurosonography”.[5,6] However, to the best of our knowledge, the standardization of reporting suspected findings during routine scans has not been implemented yet. An appropriate interpretation and standardized description of abnormal US findings may have a significant impact not only on the management of referrals, but also on the training of obstetricians. Ultimately, adopting a standardized approach can help to reduce the burden of false positive cases. Hence, the scope of these guidelines is to establish a consensus regarding the description and interpretation of the US abnormal findings in each trimester suggestive of the most common CNS anomalies. All anatomical structures and measurements of the fetal brain and spine recommended in the WAPM Practice Guidelines on fetal CNS examination between 11 + 0 to 14 + 0 weeks’ gestation and at the mid-trimester US scan.[1,3] were listed and the most common descriptions of the US abnormal findings were reported for each item. Group members were asked to reach a consensus on the description of each finding to establish a standardized reporting, and to point out which signs may appear late in pregnancy requiring a third trimester evaluation. For each US abnormal finding, agreement among members was assessed. Only items for which consensus exceeding 75% agreement among members are reported in this document. If no initial agreement was reached, members were asked to vote again after discussion. Reference studies were reviewed and evaluated to assess evidence quality according to the method outlined by the U.S. Preventive Services Task Force.[7]

CNS examination in routine practice

All the recommendations were: Evidence level III, Strength of recommendation Level C.

1.First trimester examination of the CNS in routine practice

Recommendation 1: The suspicious findings concerning the fetal CNS at the routine first trimester examination should be reported as listed in Table 1.

1) Skull Ossification
Under normal conditions, the fetal skull appears as an oval-shaped hyperechoic bony structure (Fig. 1).[3]

Technical issues: Recognition of small cranial meningoceles by antenatal ultrasound may be challenging. In addition, basal cephaloceles protruding through the base of skull are inaccessible to antenatal sonography (Fig.1C).

2) Cerebral Hemispheres
The two hemispheres, similar in size, are separated by a straight, uninterrupted midline echo (interhemispheric fissure) on the axial planes. The choroid plexuses should fill the two lateral ventricles on the sides of the midline (butterfly sign on axial view) occupying roughly half or more of the ventricle length/area (Fig. 1A).[3]

Technical issues:In the first trimester only severe forms, alobar and semilobar varieties, are usually detected (Fig.2).

3) Cranial Posterior Fossa
On the sagittal view of the fetal brain, the anechoic round-shaped diencephalon is visible and the cranial posterior fossa structures are just posterior to it, including the brainstem, the 4th ventricle and the cisterna magna, appearing as three anechoic spaces, roughly similar in size (Fig.3).[3]

Technical issues: On a routine basis, the width of each of the three spaces should be qualitatively evaluated, as these spaces are normally expected to be similar in size. However, measurement of the spaces and ratio between the width of the brainstem and the space behind it (BS/BSOB) could be helpful when the three spaces seem abnormal.[8] With high-frequency transvaginal probe, the brain stem does not appear anechoic but shows echogenicity similar to that of the brain tissue.

4) Fetal Spine
The fetal spine typically appears as linear structure, composed of a continuous sequence of vertebrae, covered by the uninterrupted skin (Fig. 4). The spine could bend according to the fetal movements, but no disruptions or interruptions of the vertebral lines or overlying skin should be visualized in normal conditions.

Technical issues: To reliably assess the spine, the fetus should lie in a dorso-anterior position. The main limitation to achieve a reliable evaluation of the spine is the persistent supine fetal lie. In most cases, given enough time, the fetus will turn over during the examination. In the first trimester, a normal appearance of the spine cannot rule out all cases of open spina bifida, as some defects may not be sufficiently evident at this early stage. - Caution should be exercised when evaluating the sacrum since the lower sacral vertebras are still not calcified. 

2.Second and third trimesters examination of the CNS in routine practice

Recommendation 2: The suspicious findings concerning the fetal CNS at the mid-trimester examination should be reported as listed in Table 2.

1) Skull Ossification
Under normal conditions the skull has a regular oval shape with no bony defects (distortion or disruption) by trans-thalamic or trans- ventricular planes (Fig.5).[1] The measurement of biparietal diameter (BPD) and head circumference (HC) should be in the normal range (± 2SD), according to the chosen growth charts. A detailed neurosonographic examination should be performed for fetuses with HC greater than 2 standard deviations below or above the mean[9,10], when the skull shape is abnormal or when US beam penetrance is reduced. Several ultrasonographic abnormal findings of the skull may appear later in gestation. As a consequence, the absence of some of these abnormal signs at the mid-trimester scan does not rule out late-onset abnormalities of the shape and size of the fetal skull. Molding of the fetal head, particularly in early gestation, may be responsible for an abnormal skull shape. In case the skull shape deviates from oval, reducing transducer pressure is advisable.

In case of a BPD or HC outside the normal ranges, the chosen growth chart should be specified on the report. Fetal positioning can significantly affect the skull’s shape, with advanced gestational age and oligohydramnios also playing a role.[11] In particular, a significantly smaller BPD (dolichocephaly or elongated anteroposterior axis of the skull) could be found in breech fetuses, suggesting that HC can be considered a more reliable measurement, as less affected than BPD by head shape variations and fetal presentation.

2) Cerebral Hemispheres
Under normal conditions the cerebral hemispheres appear symmetrical and separated on the trans-ventricular plane (Fig. 5A).

Technical issues: The axial planes provide an adequate visualization of the hemisphere distal to the transducer. One of the major disadvantages of using this axial plane is the poor visualization of the hemisphere proximal to the transducer.[1] Due to this technical issue, asymmetry of the cerebral hemispheres could be difficult to be assessed using these planes. The cerebral hemispheres are completely separated by a hyperechoic straight line representing the interhemispheric fissure and the falx. The only normal interruption is at the level of the cavum septum pellucidum (CSP).

Increased distance between cerebral hemispheres (Fig. 6) has been described as an indirect sign of either complete agenesis of the corpus callosum (ACC)[12] or brain atrophy.[6] However, if not accompanied by other indirect signs these findings are frequently overlooked.

3) Falx (interhemispheric fissure)
Under normal conditions the hemispheres appear separated by a clearly visible interhemispheric fissure and falx on the trans-ventricular plane (Fig. 5A and 7A).

Technical issues: Distortion of the interhemispheric fissure is commonly subtle (Fig. 7B) and challenging to assess based solely on axial views. Consequently, at the mid-trimester anomaly scan its evaluation could be limited.

4) Lateral ventricles: occipital horns (atrium)
Under normal conditions the occipital horns of the lateral ventricles appear as sonolucent structures with the echoic choroid plexuses filling the ventricular bodies and atria (Fig. 7A). Measurement of the atrial width of the lateral ventricle distal to the transducer is part of the second-trimester anatomy scan. It should not exceed 10 mm, independently from gestational age.

Technical issues: The poor visualization of the lateral ventricle proximal to the transducer (Fig. 8A) inevitably limits the detection rate of unilateral ventriculomegaly. The detection of unilateral ventriculomegaly affecting the proximal ventricle usually relies on its qualitative assessment, as the measurement is generally suboptimal. In cases where a subjective impression suggests a proximal ventricle significantly larger than the distal one (Fig. 8B), the patient should be referred for fetal neurosonography.[13,14] However, the predictive accuracy is suboptimal, with a significant number of false positive and negative cases. The teardrop shape of the lateral ventricles (colpocephaly) (Fig. 8C) has been described as an indirect sign of complete ACC.[12] However, if not accompanied by other indirect signs, complete ACC might be overlooked. Furthermore, the teardrop shape becomes more evident with advancing gestational age[14], which may partially explain the limited detection of ACC if not directly assessed on the midsagittal view.

5) Lateral ventricles: frontal horns
Under normal conditions the anterior portion of the lateral ventricles (frontal or anterior horns) appears as two comma-shaped, fluid-filled structures separated medially by the CSP (Fig. 7A). Under normal conditions the shape of the anterior horns (AH) is comma-shaped in the vast majority of cases, but it may be triangular as well.[15] A square shape of the AH (Fig. 9) may be an important clue of abnormal cortical development. The optimal assessment of the frontal horns orientation requires a coronal view. Therefore, although an abnormal shape or distance between the AHs could be associated to CNS anomalies (such as ACC), it has not been included among the abnormal US signs to report.

6) Cavum septum pellucidum
Under normal conditions the CSP is detected as a fluid-filled cavity between two thin membranes located between the frontal horns of the lateral ventricles (Fig. 7A).

Technical issues: A common mistake is to consider the columns of the fornix as the CSP, possibly missing many CNS anomalies.[16,17] When the CSP is present, the columns of the fornix are seen on a plane just below the CSP. Although the hypoechoic appearance of the columns of the fornix may resemble the CSP, the identification of a parallel “line” in the center of this hypoechoic structure helps to differentiate between the fornix and CSP. The columns of the fornix appear as two hypoechoic structures with a central interface reflection (Fig. 10), whereas the CSP is a rectangular box-like structure located between the AH (Fig. 7A). Another artifact is due to the US beam crossing the walls of the frontal horns, normally in close proximity, and generating linear echoes that mimic the presence of a CSP within the ventricular cavity.[16,18]
Abnormal shape and size of the CSP has been described as potentially associated to cerebral[19] and genetic anomalies.[20,21] However, the evaluation of the CSP shape is extremely subjective and measurement of the CSP is not part of the mid-trimester routine anatomy scan.[1] 

7) Corpus Callosum (CC)
The CC appears as a hypoechoic midline structure at US by median/mid-sagittal plane of the fetal brain. Under normal conditions the CC is present with all its components, going front to back: rostrum, genu, body and splenium (Fig. 11).

Technical issues: At the mid-trimester scan, the CC should be entirely visualized but its measurement is not required. When a median/mid-sagittal plane of the fetal brain is properly obtained, the patient should be referred if the CC subjectively appears shorter due to the lack of some of its components. The evaluation of the CC thickness is not required at the mid-trimester routine US evaluation as the significance and prognosis of an isolated thick CC remains unknown due to the lack of definitive data [22]. Agreement among experts has not been reached on this issue, and abnormal thickness of CC should not be reported at the mid- trimester routine US scan. The visualization of the pericallosal artery on the mid-sagittal view by color Doppler could be a useful hint of the presence of the CC.

Moreover, these abnormal findings, when isolated, have unclear significance and have been described as a normal variant. Thus, consensus among experts has not been reached and abnormal shape and size of the CSP should not be reported at the mid-trimester routine US scan.

8) Thalami
Under normal conditions two thalami separated from each other in the midline are detectable (Fig. 5A).

Technical issuesSince the third ventricle (Fig. 12) is in many cases very thin frequently the thalami appeared “fused”, however holoprosencephaly never involves only the thalami.

9) Insula
In the early second trimester, the Sylvian fissure (SF) appears as a smooth-margined, shallow notch on the lateral side of the cerebral hemisphere (Fig. 7A). Over the course of the subsequent weeks of pregnancy, the morphology of this structure changes, showing a more prominent indentation with distinct angularity.

Technical issues: SF operculization is a fetal brain gyration feature easily assessed prenatally by ultrasound.[23] Even if the SF is always visible on the standard trans-thalamic plane, in case of abnormal cortical development the SF shape changes at around 20 weeks of gestation may be very subtle[24], as abnormal SF opercularization usually becomes more evident after 24 weeks’ gestation. In case of abnormal SF shape, a multiplanar approach to the fetal brain, which is not part of the second trimester anatomy scan, should be considered for a reliable assessment of the SF and cortex.  

10) Cerebellum
Under normal conditions on the axial plane the cerebellum appears as a butterfly shaped structure (Fig. 13) formed by the round cerebellar hemispheres joined in the middle by the more echogenic cerebellar vermis. The cerebellar hemispheres should be homogeneous and symmetrically round-shaped[25], with smooth borders.

Technical issues: At the mid-trimester scan the cerebellar vermis completely covers the fourth ventricle, clearly separated from the cisterna magna. However, if the US beam includes the lower part of the cerebellum with an excessive caudal angulation, the plane will cut through the inferior part of the fourth ventricle rather than the vermis. The juxtaposition of the fluid-filled vallecula cerebelli with the adjacent cerebellar hemispheres creates the impression of a continuum between the cisterna magna and the fourth ventricle, mimicking hypoplasia/partial agenesis of the vermis.

11) Cerebellar Vermis
Under normal conditions the cerebellar vermis appears as a more echogenic structure located between the cerebellar hemispheres on an axial scan (Fig.14A). On the median/mid-sagittal plane the entire cerebellar vermis is visible, completely covering the fourth ventricle and appearing in direct contact with the brainstem (Fig. 14B).

Technical issues: Using high-frequency ultrasound transducers improves the ability to differentiate the 4th ventricle choroid plexus (4V-CP) from the inferior border of the vermis. 4V-CP appears more echogenic than the vermis and attaches to the vermis’ inferior part, directly in contact with the brainstem.[26] 

The presence of a communication between the 4th ventricle and the cisterna magna in the midsagittal plane (Fig.15) is relatively common during the 2nd trimester due to the still incomplete rotation of the vermis.

12) Cisterna Magna (CM)
Under normal conditions the cisterna magna or cisterna cerebello-medullaris (CM) is a fluid filled space posterior to the cerebellum (Fig.14A). The antero-posterior diameter of the cisterna magna should not exceed 10 mm.

Technical issues: Thin septations in the CM are normal structures (Fig.16) and should not be confused with any malformations of the posterior fossa.[27] The use of an angled semi-coronal plane may create the false appearance of an enlarged cisterna magna.

13) Spine
Under normal conditions the spine appears as an S-shaped line without any abnormal curvatures, and the skin above the spine appears continuous without interruption (Fig.17A).

References

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16. Pilu G, Tani G, Carletti A, Malaigia S, Ghi T, Rizzo N. Difficult early sonographic diagnosis of absence of the fetal septum pellucidum. Ultrasound Obstet Gynecol 2005; 25:70–72. [PubMed] [CrossRef]
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26. Shinar S, Har-Toov J, Lerman-Sagie T, Malinger G. Thick corpus callosum in the second trimester can be transient and is of uncertain significance. Ultrasound in Obstetrics and Gynecology, 2016, 48(4), 452–457. [PubMed] [CrossRef]
27. Quarello E, Stirnemann J, Ville Y, Guibaud L. Assessment of fetal Sylvian fissure operculization between 22 and 32 weeks: A subjective approach. Ultrasound in Obstetrics and Gynecology, 2008, 32(1), 44–49. [PubMed] [CrossRef]
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	File/Dsecription
	Figure-1A A) Normal fetal head and brain at 13 weeks' gestation. The hyperechoic oval-shaped skull is visible. The cerebral hemispheres are separated by the interhemispheric fissure (arrows). Lateral ventricles (*) containing choroid plexuses (C) are also visible.
	Figure-1B Cranial bone defect: the cranial vault is absent (acrania).
	Figure-1C Cranial bone defect: a skull defect is localized in the frontal region (cephalocele) with a cystic formation (arrows) protruding through the defect
	Figure-2 Incomplete separation of cerebral hemispheres: transverse view of the head showing the fusion of the thalami and the presence of a single midline ventricle (alobar holoprosencephaly).
	Figure-3A Sagittal view of the fetal head and brain. A) Normal aspect of the posterior fossa: the brainstem (BS), the 4th ventricle (4V), and the cisterna magna (*) appear as three anechoic spaces, roughly similar in size (D: the diencephalon)
	Figure-3B Sagittal view of the fetal head and brain: Two instead of three spaces are detectable in the posterior fossa in this fetus with open spina bifida
	Figure-3C Sagittal view of the fetal head and brain: Anechoic spaces in the posterior fossa are not similar in size: the 4V is bigger than the other ones in this fetus with a cyst of the posterior fossa
	Figure-4A Midsagittal view of the fetal spine. A) Normal aspect of the fetal spine in the 1st trimester: it appears as linear structure, composed of a continuous sequence of vertebrae, covered by the uninterrupted skin
	Figure-4B Midsagittal view of the fetal spine: An interruption of the cutaneous contour and a cystic mass are detected in this fetus with open spina bifida
	Figure-5A Trans-thalamic plane. A) Normal aspect of the skull with a regular oval shape and no bony defects
	Figure-5B Trans-thalamic plane: Abnormal shape of the fetal head (not oval): this is the typical lemon sign in a fetus with open spina bifida
	Figure-5C Trans-thalamic plane: Cranial bone defect: cystic formation protruding through a skull defect (arrow), localized in the occipital region (cephalocele)
	Figure-6A Incomplete separation of cerebral hemispheres and the interhemispheric fissure is absent: axial scan at the level of the thalami showing absence of midline structures and fused thalami in a fetus with alobar holoprosencephaly
	Figure-6B Increased distance between cerebral hemispheres: this is an indirect sign of the complete agenesis of corpus callosum showing an increased separation of the hemispheres with the bodies of the lateral ventricles parallel to each other and shifted laterally
	Figure-7A The trans-ventricular plane in a normal fetus: the interhemispheric fissure (IH), cavum septi pellucidi (CSP), two frontal horns (*), falx and insula (arrow) can be assessed
	Figure-7B Distortion of the interhemispheric fissure (arrows)
	Figure-8A The atrial width of the distal ventricle is increased (≥ 10 mm) in a fetus with mild ventriculomegaly
	Figure-8B The atrial width of the proximal ventricle appears significantly larger than the distal one in a fetus with unilateral ventriculomegaly affecting the proximal ventricle
	Figure-8C The lateral ventricle has a teardrop shape (colpocephaly): this is an indirect sign of the complete agenesis of corpus callosum
	Figure-9A The frontal horns (*) appear fused due to the agenesis of the CSP
	Figure-9B The shape of the frontal horns (*) doesn't look normal: the square shape of the frontal horns is visible in this fetus with cortical anomaly
	Figure-10A The CSP is not visible in the trans-ventricular plane in this case of complete agenesis of the corpus callosum
	Figure-10B A plane just slightly inferior to the trans-ventricular one: the columns of the fornix are visible (arrows)
	Figure-11A Trans-frontal view in a normal fetus showing simultaneously the facial profile, the corpus callosum (CC) and the cerebellar vermis (v)
	Figure-11B The corpus callosum is not visible in this case of complete agenesis of the corpus callosum.
	Figure-12 Trans-thalamic plane showing an anechoic structure (*) between the two thalami in this fetus with triventricular hydrocephalus
	Figure-13A Normal trans-cerebellar plane showing the cerebellum (C) as a butterfly shaped structure and behind the cerebellum, the cisterna magna (CM)
	Figure-13B The shape of the cerebellum (C) doesn't look normal ("banana sign") and the cisterna magna obliterated in this case of open spina bifida
	Figure-13C A cleft (arrow) is present between the hemispheres (ce) and the cerebellar vermis does not completely cover the fourth ventricle in this fetus with a cyst of the posterior fossa
	Figure-14A The normal aspect of the cerebellar vermis (V) in an axial plane: it appears as a more echogenic structure located between the cerebellar hemispheres. The fourth ventricle (*) is visible, with the vermis (V) and the cisterna magna (CM) behind it
	Figure-14B The normal aspect of the cerebellar vermis (V) in the median/midsagittal plane: it completely covers the fourth ventricle and appeared to be in direct contact with the brainstem (BS). (*: the fourth ventricle; CC, corpus callosum)
	Figure-15A Abnormal aspect of the cerebellar vermis in an axial plane: the cerebellar vermis is absent and cerebellar hemispheres are fused in this case of Rhombencephalosynapsis
	Figure-15B Abnormal aspect of the cerebellar vermis in the midsagittal view of the posterior fossa showing an upward displacement of the vermis (V) and an open fourth ventricle, communicating with the cisterna magna. The vermis (V) is not in direct contact with the brainstem (BS)
	Figure-16A The antero-posterior diameter (yellow dashed line) of the cisterna magna is > 10 mm in this fetus with a megacisterna magna
	Figure-16B Thin septations (arrows) in the cisterna magna are normal structures
	Figure-17A Normal aspect of the fetal spine in the midsagittal view: the spine appears as an S-shaped line without any abnormal curvatures and the skin above the spine appears continuous without interruption
	Figure-17B The spine appears irregular
	Figure-17C A cystic mass (arrows) is detected at the caudal end of the spine in this case of spina bifida
	Table-1 Suspicious findings to be reported at the first trimester examination
	Table-2 Suspicious findings to be reported at the mid-trimester examination